Key takeaways:
- Vutrisiran improved all-cause mortality and recurrent CV independent of disease severity in cardiac amyloidosis.
- Regardless of cutoffs, vutrisiran also improved various health and quality of life endpoints.
CHICAGO — Vutrisiran improved mortality and recurrent CV risks independent of disease severity and improved several other endpoints for a broad spectrum of patients with transthyretin amyloidosis with cardiomyopathy, subgroup analyses show.
“Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive disease [that] sadly impairs the quality of life, functional capacity and health status of patients, as described by themselves as well as through objective testing,” Farooq H. Sheikh, MD, attending physician in the Advanced Heart Failure Program at MedStar Heart & Vascular Institute at Georgetown University School of Medicine, told Healio. “Vutrisiran has demonstrated, for the first time, that an RNA interference therapeutic drug given subcutaneously can improve these outcomes.”
In the phase 3, randomized, double-blind, placebo-controlled, multicenter HELIOS-B study, researchers randomly assigned 654 patients with ATTR-CM to vutrisiran 25 mg (Amvuttra, Alnylam; n = 326) or placebo (n = 328) every 3 months for up to 36 months. In addition, a 6-minute walk test and Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) were completed at baseline and every 6 months. Researchers utilized cutoff values of decreases from baseline more than 7 m, 15 m and 35 m for the 6-minute walk test and more than 5 and 10 points for the KCCQ-OS as indicators of disease worsening.
The monotherapy population included 395 patients with ATTR-CM who were not receiving tafamidis (Vyndamax, Pfizer) at baseline, of whom 196 received vutrisiran and 199 received placebo.
Both analyses were presented at the American College of Cardiology Scientific Session.
Multidisciplinary Sarcoidosis Program at Stanford University School of Medicine, and colleagues evaluated vutrisiran treatment vs. placebo in patients with ATTR-CM based on baseline HF severity subgroups.
Witteles and colleagues assessed 654 patients with NYHA class I, II or III severity and by baseline N-terminal pro-B-type natriuretic peptide levels of 2,000 ng/L or higher or 2,000 ng/L or less and assessed the primary composite of all-cause mortality and recurrent CV events, all-cause mortality and additional functional and biomarker endpoints.
Overall, 12.8% of patients had class I severity, 77.7% had class II and 9.5% had class III. Median baseline NT-proBNP level was 1,920 ng/L.
Researchers observed lower all-cause mortality and recurrent CV risks among patients treated with vutrisiran with class I (HR = 0.54; 95% CI, 0.27-1.1), class II (HR = 0.77; 95% CI, 0.57-1.03) and class III (HR = 0.68; 95% CI, 0.33-1.41) vs. placebo. Similar results were also observed for patients treated with vutrisiran with NT-proBNP tertiles of 2,000 ng/L or less (HR = 0.53; 95% CI, 0.35-0.79) and more than 2,000 ng/L (HR = 0.8; 95% CI, 0.56-1.13).
“Two things are simultaneously true: Treatment with vutrisiran worked in the population studied regardless of the stage of heart failure, and the treatment is probably most effective when instituted earlier in the disease. So what does that mean?” Witteles told Healio. “It’s important to have a high level of suspicion to diagnose ATTR-CM as early as possible, but patients should be offered treatment even with relatively later stages of disease.”
In the monotherapy population of patients not on tafamidis at baseline, all-cause mortality and recurrent CV risks were also lower for patients treated with vutrisiran vs. placebo.
“We now have multiple effective treatment options for ATTR-CM, but we can’t treat patients who aren’t diagnosed,” Witteles told Healio. “So, No. 1 on the list remains researching ways to move the diagnosis earlier, and to determine the appropriate populations to screen for the disease.”
Improved functional capacity, QOL
In the second prespecified analysis, researchers expanded on results from secondary endpoints in the HELIOS-B study by evaluating the efficacy of vutrisiran on functional capacity, health status and quality of life for patients with ATTR-CM.
“What we found was that the percentage of patients that had been randomly selected to receive vutrisiran vs. placebo were much more likely to maintain or even improve both their functional capacity and quality of life,” Sheikh told Healio. “In addition, a significant number of patients were able to do so with robust stabilization or even improvement in these metrics, as measured by previously published measures.”
In the overall population, during a 30-month follow-up period, more patients treated with vutrisiran vs. placebo maintained or improved 6-minute walk test distance independent of cutoffs of more than 7 m (49.6% vs. 33.2%), more than 15 m (55.5% vs. 38.6%) and more than 35 m (68.4% vs. 51.6%).
In addition, compared with placebo, more patients treated with vutrisiran maintained or improved KCCQ-OS score with cutoff values of more than 5 points (46.6% vs. 63.5%) or more than 10 points (60.7% vs. 74.6%).
Across subgroups, patients treated with vutrisiran had more favorable changes vs. placebo in terms of least squares mean difference in change from baseline for KCCQ-OS subdomains and 6-minute walk test distance and KCCQ-OS
“Despite finding these patients earlier in the disease, this clinical trial demonstrated the ability to improve survival and reduce the risk of cardiovascular events,” Sheikh told Healio. “I would argue, for a patient population whose mean age is 77 years, people want not only to live longer, but they want to feel better. They want quality of life, as they measure it to be better, and we were able to show that that was achieved over a 30-month follow-up period.”
Researchers observed similar benefits with vutrisiran treatment in the monotherapy population.
“It is our goal to identify more patients earlier in the disease, so that they don’t suffer the ravages of the disease and need rescuing but instead apply these now established FDA-approved treatments to improve the outcome for these patients,” Sheikh told Healio. “Through the clinical HELIOS-B, investigators, including myself, have shown that this intervention, treatment with a drug called vutrisiran, reduces the risk of mortality or dying from the disease as well as having adverse cardiovascular events.”